Background: Combining anti-angiogenic drugs with immune checkpoint inhibitors (ICI) after progression on ICIs presents a promising therapeutic approach in renal cell carcinoma (RCC). Atezolizumab (anti-PD-L1 mAb) has shown activity in combination with anti-angiogenic therapy after prior progression with ICI. Cabozantinib (VEGFR-TAM-TKI), a standard of care therapy in RCC, promotes an immune-permissive environment and may enhance atezolizumab activity. In phase Ib COSMIC-021, cabozantinib + atezolizumab safety and efficacy was favorable in clear-cell(cc) RCC and non(n)-ccRCC (Pal et al [702O] and McGregor et al [709P], ESMO 2020). The phase III CONTACT-03 study is further evaluating cabozantinib + atezolizumab vs cabozantinib in second-line/third-line RCC after prior ICC therapy. Methods: CONTACT-03 (NCT04338269) is a phase III, open-label, randomized, multicenter study that will enroll ≈500 patients across more than 150 sites globally. The trial opened in July 2020 and is actively recruiting adult patients with RCC. Key inclusion criteria include histologically confirmed locally advanced or metastatic ccRCC or nccRCC (papillary or unclassified); radiographic disease progression during or following first-line/second-line ICI treatment; measurable disease (RECIST 1.1); KPS score ≥70%; and availability of an archival tumor specimen and fresh biopsy (if clinically feasible). Patients must have adequate hematological and end organ function. Prior ICI therapy must be a PD-1/PD-L1 inhibitor (mono- or combination therapy) and must be in the immediate preceding line of therapy. Key exclusion criteria include prior treatment with cabozantinib or a mTOR inhibitor. Patients with symptomatic, untreated, or actively progressing CNS metastases or significant other intercurrent illness are not eligible. Stratification factors are IMDC risk group (0 vs 1-2 vs ≥3); line of most recent prior ICI therapy (first vs second); and histology (dominant cc without sarcomatoid vs dominant non-cc [papillary or unclassified] without sarcomatoid vs any sarcomatoid component [cc or ncc]). Patients will be randomized 1:1 to receive atezolizumab (1200 mg/IV/q3w) plus cabozantinib (60 mg/oral/qd) or cabozantinib alone (60 mg/oral/qd) until unacceptable toxicity or loss of clinical benefit. Patients will not be allowed to crossover from the control arm to the experimental arm. Multiple primary endpoints are independent review facility (IRF)-assessed PFS and OS. Additional endpoints include investigator-assessed PFS, IRF- and investigator-assessed ORR and DOR; HRQOL, biomarkers and safety. Radiographic efficacy will be assessed per RECIST 1.1. Clinical trial information: NCT04338269.